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This study aims to determine whether 1 year of high-intensity interval training (HIIT) and omega-3 fatty acid (n-3 FA) supplementation would improve fitness, cardiovascular structure/function, and body composition in obese middle-aged adults at high-risk of heart failure (HF) (stage A).It is unclear if intensive lifestyle interventions begun in stage A HF can improve key cardiovascular and metabolic risk factors.High-risk obese adults (n = 80; age 40 to 55 years; N-terminal pro-B-type natriuretic peptide40 pg/mL or high-sensitivity cardiac troponin T0.6 pg/mL; visceral fat2 kg) were randomized to 1 year of HIIT exercise or attention control, with n-3 FA (1.6 g/daily omega-3-acid ethyl esters) or placebo supplementation (olive oil 1.6 g daily). Outcome variables were exercise capacity quantified as peak oxygen uptake (V.OFifty-six volunteers completed the intervention. There was no detectible effect of HIIT on visceral fat or myocardial triglyceride content despite a reduction in total adiposity (Δ: -2.63 kg, 95% CI: -4.08 to -0.46, P = 0.018). HIIT improved exercise capacity by ∼24% (ΔV.OOne-year HIIT improved exercise capacity, cardiovascular structure/function, and adiposity in stage A HF with no independent or additive effect of n-3 FA administration. (Improving Metabolic Health in Patients With Diastolic Dysfunction [MTG]; NCT03448185).

Background: Individuals with left ventricular (LV) hypertrophy and elevated cardiac biomarkers in middle age are at increased risk for the development of heart failure with preserved ejection fraction. Prolonged exercise training reverses the LV stiffening associated with healthy but sedentary aging; however, whether it can also normalize LV myocardial stiffness in patients at high risk for heart failure with preserved ejection fraction is unknown. In a prospective, randomized controlled trial, we hypothesized that 1-year prolonged exercise training would reduce LV myocardial stiffness in patients with LV hypertrophy. Methods: Forty-six patients with LV hypertrophy (LV septum >11 mm) and elevated cardiac biomarkers (N-terminal pro-B-type natriuretic peptide [>40 pg/mL] or high-sensitivity troponin T [>0.6 pg/mL]) were randomly assigned to either 1 year of high-intensity exercise training (n=30) or attention control (n=16). Right-heart catheterization and 3-dimensional echocardiography were performed while preload was manipulated using both lower body negative pressure and rapid saline infusion to define the LV end-diastolic pressure-volume relationship. A constant representing LV myocardial stiffness was calculated from the following: P=S×[Exp {a (V–V 0 )}–1], where “P” is transmural pressure (pulmonary capillary wedge pressure – right atrial pressure), “S” is the pressure asymptote of the curve, “V” is the LV end-diastolic volume index, “V 0 ” is equilibrium volume, and “a” is the constant that characterizes LV myocardial stiffness. Results: Thirty-one participants (exercise group [n=20]: 54±6 years, 65% male; and controls (n=11): 51±6 years, 55% male) completed the study. One year of exercise training increased max by 21% (baseline 26.0±5.3 to 1 year later 31.3±5.8 mL·min –1 ·kg –1 , P P =0.0004), whereas there was no significant change in max in controls (baseline 24.6±3.4 to 1 year later 24.2±4.1 mL·min –1 ·kg –1 , P =0.986). LV myocardial stiffness was reduced (right and downward shift in the end-diastolic pressure-volume relationship; LV myocardial stiffness: baseline 0.062±0.020 to 1 year later 0.031±0.009), whereas there was no significant change in controls (baseline 0.061±0.033 to 1 year later 0.066±0.031, interaction P =0.001). Conclusions: In patients with LV hypertrophy and elevated cardiac biomarkers (stage B heart failure with preserved ejection fraction), 1 year of exercise training reduced LV myocardial stiffness. Thus, exercise training may provide protection against the future risk of heart failure with preserved ejection fraction in such patients. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03476785.

Background: Individuals with left ventricular hypertrophy (LVH) and elevated cardiac biomarkers in middle age are at high risk for the development of heart failure with preserved ejection fraction (HFpEF). However, it is unknown what the pathophysiological underpinnings of this high-risk state may be. We tested the hypothesis that patients with LVH and elevated cardiac biomarkers would demonstrate elevated left ventricular (LV) myocardial stiffness in comparison with healthy controls as a key marker for future HFpEF. Methods: Forty-six patients with LVH (LV septum >11 mm) and elevated cardiac biomarkers (N-terminal pro-B-type natriuretic peptide [>40 pg/mL] or troponin T [>0.6 pg/mL]) were recruited, along with 61 age- and sex-matched (by cohort) healthy controls. To define LV pressure-volume relationships, right heart catheterization and 3-dimensional echocardiography were performed while preload was manipulated using lower body negative pressure and rapid saline infusion. Results: There were significant differences in body size, blood pressure, and baseline pulmonary capillary wedge pressure between groups (eg, pulmonary capillary wedge pressure: LVH, 13.4±2.7 versus control, 11.7±1.7 mm Hg, P P =0.028). Conclusions: LV myocardial stiffness in patients with LVH and elevated biomarkers (stage-B HFpEF) is greater than in age- and sex-matched controls and thus appears to represent a transitional state from a normal healthy heart to HFpEF. Although the LV myocardial stiffness of patients with LVH is greater than that of healthy controls at this early stage, further studies are required to clarify whether interventions such as exercise training to improve LV compliance may prevent the full manifestation of the HFpEF syndrome in these high-risk individuals. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT03476785 and NCT02039154.

Introduction: Heart failure with preserved ejection fraction (HFpEF) patients exhibit a marked rise in PCWP during exercise, which may contribute to ventilation-perfusion (V/Q) mismatch and manifest as an increase in alveolar dead space (alveolar V D ) and alveolar-arterial PO 2 difference (AaPO 2 ). Nitrates reduce PCWP during exercise in HFpEF, but whether nitrates also reduce V/Q mismatch during exercise is unknown. Hypothesis: The increase in PCWP and V/Q mismatch during exercise would be attenuated with acute nitroglycerin (NTG) treatment compared with placebo in HFpEF patients. Methods: 13 patients performed a 6min cycling test at 20W and an incremental cycling test (with right-heart and arterial catheterization) with placebo and NTG treatment. The physiologic dead space to tidal volume (V D /V T ) was calculated using the Enghoff modification of the Bohr equation. Alveolar V D was calculated as: V D /V T x V T - anatomic dead space (anatomic V D , estimated as 2mL/kg lean body mass). AaPO 2 was calculated using the alveolar gas equation. Data were analyzed using a 2-way ANOVA. Results: PCWP decreased with NTG at 20W (placebo: 21.1±6.2 vs. NTG: 16.5±6.1mmHg, p=0.02) and peak exercise (placebo: 33.7±7.1 vs. NTG: 26.2±5.6mmHg, pD did not differ between treatments at rest (placebo: 0.11±0.07 vs. NTG:0.12±0.06L/breath, p=0.91), 20W (placebo: 0.22±0.09 vs. NTG: 0.24±0.10L/breath, p=0.62), or peak exercise (placebo: 0.34±0.14 vs. NTG:0.36±0.16L/breath, p=0.83). Nor did AaPO 2 differ between treatments at rest (placebo: 17.6±4.3 vs. NTG: 18.3±5.7mmHg, p=0.76), 20W (placebo: 22.0±6.9 vs. NTG: 22.1±8.1mmHg, p=0.99), or peak exercise (placebo: 25.1±9.1 vs. NTG: 27.8±9.9mmHg, p=0.41). No significant exercise-by-treatment interaction was detected for V D /V T (p=0.80). Conclusions: This study showed that NTG attenuated the increase in PCWP, but had no effect on the increase in alveolar V D or AaPO 2 during exercise. These findings suggest that the exercise-induced increase in V/Q mismatch may not be exclusively related to abnormal exercise hemodynamics. Further study is required to determine the clinical consequences and the mechanism(s) responsible for the progressive increase in V/Q mismatch during exercise in HFpEF patients.

Background: Low aerobic power (peak VO 2 ) is common in patients with Heart Failure with preserved Ejection Fraction (HFpEF). Mechanisms for low VO 2 are diverse and vary between patients. We used the cardiac output (Qc) response to VO 2 during exercise to characterize patients with HFpEF into those with primary cardiac or peripheral defects in oxygen uptake. Methods: Patients with HFpEF (n =15, age 69±6 years) underwent invasive cardiopulmonary exercise testing with measures taken at rest, 20W, and peak exercise. A right heart catheter was used to measure end-expiratory PCWP and cardiac output (Qc, direct Fick). Oxygen uptake (VO 2 ) was measured using Douglas bags. Patients were “cardiac limited” if their ΔQc/ΔVO 2 relationship was blunted (2 was normal or high (≥5). Effect size between groups was determined with Cohen’s d . Results: Seven patients were cardiac limited and eight were peripherally limited. ΔQc/ΔVO 2 slope was lower in cardiac limited patients (4.2±0.7 vs 6.6±1.3, Cohen’s d = 1.52). Cardiac limited patients were younger and more often female (Values and Cohen’s d shown in Table ). Peak PCWP was similar between the groups (C: 34±8 vs P: 33±7 mm Hg, d = 0.09). Peak VO 2 was higher in cardiac limited patients (C: 12.7±4.3 vs P 9.8±1.3 ml/min/kg, d = 0.85). Stroke volume reserve was lower in the cardiac limited patients (C: 9±18% vs P: 37±20%, d = 0.77). Peripheral oxygen extraction (ΔAVO 2 ) during exercise was lower in the peripherally limited patients (C: 13.2±1.7% vs P: 10.8±1.4%, d =1.24). Conclusions: Phenotyping exercise intolerance using the Fick equation can identify HFpEF patients with primary cardiac and peripheral limitations causing low aerobic power. Cardiac limited patients were unable to augment stroke volume, while peripherally limited patients were unable to augment the oxygen extraction from skeletal muscles. Exercise based phenotyping may be a useful strategy to match therapies to patient specific physiology.

Background: There are no proven pharmacologic strategies for HFpEF; therefore, lifestyle interventions must be developed to prevent disease progression in those at high risk for developing HFpEF (Stage A). We performed a randomized, double blind, placebo controlled trial evaluating the effect of 1-year of high intensity interval training (HIIT) and polyunsaturated fatty acid supplementation (PUFA) on key risk factors in Stage A HFpEF. Hypothesis: Long duration (1-year) HIIT and PUFA (1.6g/daily Omega-3-Acid Ethyl Esters) will reduce visceral adiposity, improve aerobic fitness, and reverse vascular stiffness in middle-aged subjects with cardio-metabolic risk factors. Methods: Individuals with stage A HFpEF (n= 73; 40-55 years; BMI>30 kg/m 2 ; visceral fat > 2 kg; NT-proBNP>40pg/ml or hscTnT>3.0 pg/ml) were randomized to HIIT + PUFA (n=22)/placebo (n=24) or yoga + PUFA (n=15)/placebo (n=19). We assessed visceral fat (DEXA), aerobic fitness (VO 2 max), cardiac output (Q C , acetylene rebreathe), peripheral oxygen extraction (a-vO 2 -difference), and arterial stiffness (pulse wave velocity and augmentation index; tonometry). Data are presented as mean change and 95% CI. Results: 1-year of HIIT decreased body fat (-1.26%, CI: -2.43 to -0.58; p=0.036) and had a similar but less consistent effect on visceral fat (-0.28 kg, CI: -0.62 to 0.04; p=0.083). Aerobic capacity increased by ~24% (ΔVO 2 : 4.41 mL/kg/min, CI: 3.22 to 5.61; pC (1.84 L/min, CI: 0.34 to 2.24; p=0.017) and a-vO 2 -difference (1.31 mL/100mL, CI: 0.13 to 2.49; p=0.031). While large elastic arterial stiffness was unchanged (PWV: -21 cm/s, CI: -61 to 19; p=0.299), augmentation index was reduced (-5.23%, CI: -9.18 to -1.35; p=0.009) indicative of improved ventricular-arterial coupling. There was no independent effect of PUFA, or interaction between HIIT and PUFA for any outcomes. Conclusions: 1-year HIIT improved leanness, aerobic fitness, peak Q C and a-vO 2 -difference, and ventricular-arterial coupling in middle-aged Stage A HFpEF. There was no independent or additive effect of PUFA administration. This is the first randomized trial to demonstrate that regular HIIT can reverse cardiometabolic impairments in Stage A HFpEF.

The half-lives of the liver mitochondrial enzymes, ornithine aminotransferase (L-ornithine: 2-oxo acid aminotransferase, EC 2.6.1.13) and cytochrome oxidase (ferrocytochrome c : oxygen oxidoreductase, EC 1.9.3.1), have been determined under basal conditions by injecting rats with NaH 1 4 CO 3 and following the decay in specific radioactivity of arginine isolated from the purified enzymes. This technique gave half-lives for the two enzymes of 1.9 and 5.7 days, respectively. An identical half-life was obtained for cytochrome oxidase using δ-amino [ 3 H]levulinate as a tracer, thus indicating that the heme and apoprotein moieties of this enzyme turn over at the same rate. The degradation rate constant of ornithine aminotransferase under induced, steady-state conditions, i.e. in rats fed a diet containing 80% of casein, was not significantly different from that under basal conditions; hence, the increased amount of enzyme present under these conditions must be due to an increased rate of synthesis. Fractionation of mitochondria with digitonin and Lubrol WX, and comparison with marker enzymes, indicated that ornithine aminotransferase is located within the mitochondrial matrix.

Several isotopic methods for the measurement of liver protein turnover were compared in a study of plasma albumin and the mixed hepatic proteins during liver regeneration. In albumin after the administration of [14C]carbonate, the rate of decay of the radioactivity of the intact protein was similar to that of arginine isolated therefrom, whereas after the administration of [guanidino-14C]arginine, the decay rate was 30% slower than that obtained with [14C]carbonate. When [guanidino-14C]arginine is given, the extrahepatic tissues, such as muscle and the plasma globulins, are labeled more heavily than the liver proteins. It is likely that the reutilization of this extrahepatic arginine by the liver accounts for the slower disappearance of radioactivity from albumin. Similar results were obtained with the mixed, indigenous hepatic proteins. In animals that had been partially hepatectomized, the decay in radioactivity in arginine after [14C]carbonate administration showed that the rate of protein breakdown was reduced by 30 % during the first 5 days of liver regeneration. There was no decay in radioactivity in similar animals given [guanidino-14C]arginine, suggesting a massive transfer of labeled extrahepatic protein arginine into the liver during regeneration.